Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• This invention relates to novel 1 -(dihydronaphthalenyl)pyridone thiazoles which are antagonists at the melanin-concentrating hormone receptor 1 (MCHR1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of obesity and diabetes.
• MCHR1 melanin-concentrating hormone receptor 1
• Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness.
• melanin-concentrating hormone originates in the hypothalamus and has orexigenic action (see Nature, Vol. 396, p. 670 (1998), for example). There is an ongoing need for the development of a melanin-concentrating hormone antagonist useful in the treatment of obesity and other associated or related diseases and conditions.
• the present invention relates to compounds according to Formula (I), and pharmaceutically acceptable salts thereof.
• A is selected from the group consisting of Formula (II) and Formula (III), II III
• Y is C, O, S, S0 2 or NR 6 ;
• p is 0-2, provided that when p is 0, Y is C;
• s 0-4;
• R 2 and R 3 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from the group consisting of O, N and S, which ring is optionally substituted one to three times, independently, by R 6 ;
• R and R are each independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl(Ci-C 3 )alkyl, hydroxyl, (Ci-C 3 )alkoxy, hydroxyl(Ci-C 3 )alkyl, and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl;
• t is 0-4, provided that when t is 0, R 5 is not halo;
• R 4 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl(Ci-C 3 )alkyl, (Ci-C 3 )alkoxyl, hydroxyl(Ci-C 3 )alkyl, or (Ci- C 3 )alkoxy(Ci-C 3 )alkyl;
• composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound of Formula (I) or salt thereof and one or more excipients.
• a method of treatment comprising the administering to a mammal, particularly a human, a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and at least one excipient, wherein said treatment is for obesity, diabetes, depression, or anxiety.
• a process for preparing a compound of Formula (I) or pharmaceutically acceptable salt thereof is also provided.
• the present invention relates to compounds of Formula (I) as shown above.
• the present invention also relates to compound of claim 1 according to Formula (IV):
• w 0-2;
• n 0-3;
• each R 9 is independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -C 6 )cycloalkyl(Ci-C 3 )alkyl, hydroxyl, halo, (Ci-C 3 )alkoxy, hydroxyl(Ci- C 3 )alkyl, and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• the present invention also relates to compound of claim 1 according to Formula (V):
• n 0-3;
• n 0-2;
• each R 1 is independently selected from the group consisting of hydrogen, halo, (Ci- C 3 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxyl(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy(Ci-C 3 )alkyl, (Ci- C 3 )alkoxy, (Ci-C 3 )haloalkyl, amino, and CN; each R 9 is independently selected from the group consisting of hydrogen, (Ci- C 6 )alkyl, (C 3 -C 6 )cycloalkyl(Ci-C 3 )alkyl, hydroxyl, halo, (Ci-C 3 )alkoxy, hydroxyl(Ci- C 3 )alkyl, and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• the present invention also relates to compound of claim 1 according to Formula (VI):
• n 0-2;
• each R 1 is independently selected from the group consisting of hydrogen, halo, (Ci- C 3 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxyl(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, (Ci-C 3 )haloalkyl, amino, and CN;
• the present invention also relates to compound of claim 1 according to Formula
• Y is C, O, S0 2 or R 6 ;
• p is 0-2, provided that when p is 0, Y is C;
• s 0-4;
• R" and R' are each independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl(Ci-C 3 )alkyl, hydroxyl, (Ci-C 3 )alkoxy, hydroxyl(Ci-C 3 )alkyl, and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• the present invention also relates to compound of claim 1 according to Formula
• n 0-2;
• each R 1 is independently selected from the group consisting of hydrogen
• each R 2 are independently selected from the group consisting of hydrogen
• the present invention also relates to compound of claim 1 according to Formula (IX):
• t is 0-4, provided that when t is 0, R 5 is not halo;
• n 0-2;
• each R 1 is independently selected from the group consisting of hydrogen
• R 4 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, hydroxyl(Ci-C 3 )alkyl, and (Ci- C 3 )alkoxy(Ci-C 3 )alkyl;
• the present invention also relates to compound according to Formula (IX):
• t is 0-4, provided that when t is 0, R 5 is not halo;
• n 0-2;
• each R 1 is independently selected from the group consisting of hydrogen, halo, (Ci-C 3 )alkyl, hydroxyl(Ci-C 3 )alkyl, and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• R 4 is hydrogen or (Ci-C 6 )alkyl;
• R" and R' are independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C 3 -C6)cycloalkyl(Ci-C 3 )alkyl, hydroxyl, (Ci-C 3 )alkoxy, hydroxyl(Ci- C 3 )alkyl, and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
• this invention relates to compounds of Formula (I), (IV), (V), (VI), (VII), (VIII), or (IX), wherein n is 1 and R 1 is halo, (Ci-C 3 )alkyl or hydroxyl(Ci- C 3 )alkyl, or a pharmaceutically acceptable salts thereof.
• this invention relates to compounds of Formula (VII),
• n 1 2 wherein n is 1 ; R is halo, (Ci-C 3 )alkyl or hydroxyl(Ci-C 3 )alkyl; Y is C; p is 0, 1 or 2; R is (Ci-C 3 )alkyl, hydroxyl or (Ci-C 3 )alkoxy; or a pharmaceutically acceptable salts thereof.
• this invention relates to compounds of Formula (IV), wherein n is l or 2; R 1 is halo, (Ci-C 3 )alkyl or hydroxyl(Ci-C 3 )alkyl; Z is O; w is 1 or 2; m is 1 ; R 9 is hydrogen, (Ci-C 3 )alkyl, hydroxyl or (Ci-C 3 )alkoxy; or a pharmaceutically acceptable salts thereof.
• salts of the present invention are pharmaceutically acceptable salts.
• Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
• Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as be
• Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybutyrates, glycolates, tartrates mande
• Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
• a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine, 2-hydroxyethylamine, 6w-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,7V- ⁇ wdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline
• salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
• These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
• the compound of Formula (I) or a salt thereof may exist in stereoisomeric forms
• the present invention includes all combinations and subsets of the particular groups defined hereinabove.
• the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F, 36C1, 1231 and 1251.
• Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability.
• 1 1C and 18F isotopes are particularly useful in PET (positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
• substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
• Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
• the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
• Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
• Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
• compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
• oral including buccal or sublingual
• rectal nasal
• topical including buccal, sublingual, or transdermal
• vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
• parenteral including subcutaneous, intramuscular, intravenous, or intradermal
• compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
• Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
• Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
• a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
• suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate,
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
• Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
• a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
• a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
• a solution retardant such as paraffin
• a resorption accelerator such as a quaternary salt
• an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
• the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
• a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
• the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
• the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
• the compound or salt of the present invention can also be combined with a free- flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
• a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.
• Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
• Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
• Suspensions can be formulated by dispersing the compound or salt of the invention in a nontoxic vehicle.
• Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
• dosage unit formulations for oral administration can be microencapsulated.
• the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
• tablets and capsules are preferred for delivery of the pharmaceutical composition.
• a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or salt thereof with at least one excipient.
• the present invention also provides a method of treatment in a mammal, especially a human, suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof.
• Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or salt thereof to said mammal, particularly a human.
• Treatment can also comprise the step of
• a therapeutically effective amount of a compound of Formula (I) or salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.
• the precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of
• a compound of Formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
• Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
• An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se. Similar dosages should be appropriate for treatment (including prophylaxis) of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
• the present invention comprises a compound of Formula (I) or salt thereof or a pharmaceutical composition thereof with at least one other anti-obesity drug and at least one anti-diabetes drug.
• anti-obesity drugs can include, for example, Metformin (or glucophage), CB1 receptor antagonists, GLP-1 agonists, opioid antagonists, and neurotransmitter reuptake inhibitors.
• a compound of the invention is employed in combination with another anti-obesity drug or anti-diabetes drug, it is to be appreciated by those skilled in the art that the dose of each compound or drug of the combination may differ from that when the drug or compound is used alone. Appropriate doses will be readily appreciated and determined by those skilled in the art.
• the appropriate dose of the compound of Formula (I) or salt thereof and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are with the expertise and discretion of the attending doctor or clinician.
• alkyl represents a saturated, straight, or branched hydrocarbon moiety, preferably having from one to twelve carbon atoms, which may be unsubstituted or substituted, saturated or unsaturated with multiple degrees of substitution included within the present invention. Suitable substituents are selected from the group consisting of halogen and hydroxyl.
• (Ci-C6)alkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms.
• alkyls include, but are not limited to methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, isobutyl, s-butyl, i-butyl, pentyl, and hexyl.
• haloalkyl refers to an alkyl group, defined hereinabove, substituted with one or more halo substituents.
• hydroxylalkyl refers to an alkyl group, defined
• cycloalkyl refers to an unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
• exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as unsubstituted and substituted versions thereof.
• alkoxy refers to the group -OR a , where R a is alkyl or cycloalkyl as defined above.
• halogen and halo represent chloro, fluoro, bromo, or iodo substituents.
• Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, including N-oxides, sulfur oxides, and dioxides.
• heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1,3-dithianyl, hexahydro-lH-l,4-diazepinyl, azabicylo[3.2.1]
• aryl aromatic, hydrocarbon, ring system.
• the ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted.
• the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system.
• a C6 ring system i.e. a phenyl ring, is a suitable aryl group.
• the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10.
• a naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group. Suitable substituents for aryl are described in the definition of "optionally substituted".
• heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
• Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
• a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
• a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
• Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
• Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
• Exemplary heteroaryl groups include but are not limited to:
• cyano refers to the group -CN.
• the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
• the phrase "optionally substituted” or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substitutent group. The phrase should not be interpreted as duplicative of the substitutions herein described and depicted.
• Exemplary optional substituent groups include acyl, alkyl, alkylsulfonyl, alkoxy, alkoxycarbonyl, cyano, halogen, haloalkyl, hydroxyl, oxo, and nitro.
• treatment includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
• Prophylaxis or prevention or delay of disease onset is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.
• the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
• therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
• therapeutically effective amounts of a compound of Formula (I), as well as salts thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
• the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M.
• compounds of invention can be prepared as illustrated in scheme 5.
• Reaction of benzyl protected pyridone with Intermediate (17) using standard copper- mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (21).
• Subsequent treatment of intermediates (21) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde intermediates (22).
• Deprotection of intermediate (22) in aqueous HC1 solution to afford intermediate (23), which reacted with intermediate (8) to afford intermediate (24).
• compounds of invention can be prepared as illustrated in scheme 6.
• Reaction of protected pyridone with intermediate (17) using standard copper-mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (25).
• Subsequent treatment of intermediates (25) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde (26).
• Deprotection of intermediate (26) using Zinc in acetic acid afforded intermediate (27), which reacted with intermediate (8) to provide intermediate (28).
• Intermediate (28) was hydrolyzed in sodium hydroxide to afford benzyl alcohol (29).
• n-BuLi 2.5 M, toluene, 280 mL, 702 mmol
• a solution of diisopropylamine 70 g, 702 mmol
• THF 1000 mL
• a solution of 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile 100 g, 584 mmol
• a solution of phenyl triflimide 250 g, 702 mmol
• THF 1000 mL
• reaction mixture was diluted with DCM (1.5 L) and washed with saturated aqueous citric acid (100 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na 2 S0 4 , filtered and evaporated in vacuo.
• the reaction was stirred at -80 °C for 30 min and then quenched by dropwise addition of MeOH (5 mL).
• the reaction mixture was diluted with DCM (30 mL) and washed by saturated aqueous citric acid (10 mL). The layers were separated and the aqueous phase was back- extracted with DCM (2 x 10 mL).
• Step 1 4-Ethyl-thiazole-2-carboxylic acid ethyl ester
• Step 1 4,5-Dimethyl-thiazole-2-carbaldeh de
• Step 1 l-Bromo-3-methyl-butan-2-one
• Step 2 4-Isopropyl-thiazole-2-carboxylic acid ethyl ester
• Step 3 (4-Isopropyl-thiazol-2-yl)-m thanol
• 4-isopropyl-thiazole-2-carboxylic acid ethyl ester (4 g, 20.07 mmol) in MeOH (100 mL) was added NaBH 4 (3.8 g, 100 mmol) at 40 °C with stirred for 24 hr.
• Step 1 Benzoic acid cyanomethyl ester
• Step 2 Benzoic acid thiocarbamoylmethyl ester
• Step 3 2-Benzoyloxymethyl-thiazole-4-carboxylic acid ethyl ester
• Step 3 tert-Butyl tetrahydro-2H-thiopyran-4-ylcarbamate
• Step 4 tert-Butyl (l ,l-dioxidetetrahydro-2H-thiopyran-4-yl)carbamate
• Step 5 1 , 1 -D ioxo-tetrahydro- 1 ⁇ 6 -thiopyran-4-ylamine
• Step 1 tert-Butyl 4-(2-(methylsulfonyl)ethyl)piperazine-l-carboxylate
• Step 2 l-(2-(Methylsulfonyl)ethyl iperazine hydrochloride A mixture of tert-butyl 4-(2-(methylsulfonyl)ethyl)piperazine-l-carboxylate (1.2 g, 4.1 mmol) in HCl/MeOH (15 mL) was stirred at 0 °C for lhour.
• Step 1 l-Benzyl-4-(4-nitr -benzoyloxy)-pyrrolidine-2-carboxylic acid methyl ester
• Step 2 l-Benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester
• Step 3 l-Benzyl-5-hydroxymethyl- rrolidin-3-ol
• Step 1 teri-Butyl 4-hydroxypiperidine- 1 -carboxylate
• Step 2 tert-Butyl 4-methoxypiperidine- 1 -carboxylate
• Step 3 4-Methoxypiperidine, Trifluoroacetic acid salt
• Example 1 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4- methyl- thiazol-2-ylmethoxy)- lH- ridin-2-one.
• Example 2 l-(6- ⁇ [(2,3-Dihydroxy-propyl)-methyl-amino]-methyl ⁇ -3,4-dihydro- naphthalen -2-yl)-4-(4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one.
• Example 3 4-((4-Methylthiazol-2-vl)methoxy)- 1 -(6-(morpholinomethyl)-3 ,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one.
• Example 4 (S)- 1 -(6-((3-Fluoropyrrolidin- 1 -yl)methyl)-3 ,4-dihydronaphthalen-2-yl)- 4-((4-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one, hydrochloride.
• Example 5 N-Methyl-N- ⁇ 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 - yl]-7,8-dihydro-naphthalen-2-ylmethyl ⁇ -methanesulfonamide.
• Example 6 1 -(6-(((2-Methoxyethyl)(methyl)amino)methyl)-3,4-dihydronaphthalen - 2-yl)-4-((5-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one.
• Examples 7-30 were prepared by the method described above for Example 1, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalene-2-carbaldehyde and the appropriate amine (A).
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above.
• Example 31 4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -[6-(3 -hydroxy-pyrrolidin- 1 ⁇ ylmethyl)-3 ,4 -dihydro-naphthalen-2-yl]-lH-pyridin-2-one.
• Example 32 4-((4-Ethylthiazol-2-yl)methoxy)- 1 -(6-((4-methylpiperazin- 1 - yl)methyl)-3 ,4 -dihydronaphthalen-2-yl)pyridin-2(lH)-one, 2 hydrochloride.
• Example 33 4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- ⁇ [(2-fluoro-ethyl)-methyl- methyl ⁇ -3 ,4-dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one.
• Examples 34-49 were prepared by the method described above for Example 31 , or routine variations thereof (unless otherwise indicated by alternative preparation), starting from [4-(4-ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalene-2-carbaldehyde and the appropriate amine (A).
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed Intermediates section above.
• Example 50 4-(4,5-Dimethyl-thiazol-2-ylmethoxy)-l- ⁇ 6-[(2-fluoro-ethylamino)- methyl]-3,4- dihydro-naphthalen-2-yl ⁇ -lH-pyridin-2-one.
• Example 51 4-(4,5-Dimethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 - ylmethyl)-3,4- dihydro-naphthalen-2-yl]- lH-pyridin-2-one.
• Example 52 (Table 3) were prepared by the method described above for Example 50, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester and the appropriate (A)-[6- (4-hydroxy-2-oxo-2H-pyridin- 1 -yl)-7,8-dihydro-naphthalen-2-ylmethyl]-carbamic acid tert- butyl ester.
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above.
• Example 53 4-((2-Methylthiazol-4-yl)methoxy)- 1 -(6-(pyrrolidin- 1 -ylmethyl)-3 ,4- dihydronaphthalen-2-yl)pyridin-2( lH)-one, hydrochloride.
• Example 54 1 - ⁇ 6-[(2-Fluoro-ethylamino)-methyl]-3 ,4-dihydro-naphthalen-2-yl ⁇ -4- (2-methyl -thiazol-4-ylmethoxy)- lH-pyridin-2-one.
• Examples 55-58 were prepared by the method described above for Example 53, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 2-methyl-thiazol-4-ylmethyl ester and the appropriate 1 - (6-((A)methyl)-3 ,4-dihydronaphthalen-2-yl)-4-hydroxypyridin-2( 1 H)-one.
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. Table 4. l-(6-((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-((2-methylthiazol-4- yl)methoxy)pyridin-2( 1 H)-one
• Nozzle Temp 60°C 3.15 (m, 2H), 2.99 (s, 3H),
• Example 59 4-(4-Isopropyl-thiazol-2-ylmethoxy)-l-(6-methylaminomethyl-3,4- dihydro-naphthalen-2-yl)- 1 H- ridin-2-one.
• Example 60 1 -(6-Dimethylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)-4-(4- isopropyl -thiazol-2-ylmethoxy)-lH- ridin-2-one.
• Example 61 4-(2-Ethyl-thiazol-4-ylmethoxy)-l-(6-methylaminomethyl-3,4-dihydro- naphthalen-2-yl)-lH-pyridin-2-one.
• Example 62 l-(6-((Dimethylamino)methyl)-3,4-dihydronaphthalen-2-yl)-4-((2- ethylthiazol-4- yl)methoxy)pyridin-2( lH)-one.
• Example 63 (Table 5) were prepared by the method described above for Example 59, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from (4-isopropylthiazol-2-yl)methyl methanesulfonate and the appropriate l-(6- ((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-hydroxypyridin-2(lH)-one.
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above.
• Example 64 l- ⁇ 6-[(l,l-Dioxo-hexahydro- ⁇ 6 -thiopyran-4-ylamino)-methyl]-3,4- dihydro- naphthalen-2-yl ⁇ -4-(5-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one.
• Examples 66-69 were prepared by the method described above for Example 64, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 5-methyl-thiazol-2-ylmethyl ester and the appropriate 1- (6-((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-((5-methylthiazol-2-yl)methoxy)pyridin- 2(lH)-one.
• the requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above.
• Example 70 4-(4-Chloro-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 -ylmethyl) -3, 4-dihydro-naphthalen-2-yl]-lH-pyridin-2-one.
• Example 72 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3, 4-dihydro-naphthalen-2-yl]-4- (thiazol-2-ylmethoxy)-lH-pyridin-2-one.
• Example 73 4-(5-Chloro-thiazol-2-ylmethoxy)- l- ⁇ 6-[(l,l -dioxo-hexahydro- 1 ⁇ 6 - thiopyran-4-ylamino)-methyl]- -dihydro-naphthalen-2-yl ⁇ -lH-pyridin-2-one
• Example 74 2- ⁇ 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 , 4-dihydro-naphthalen-2-yl] -2-oxo- 1 , 2-dihydro-pyridin-4-yloxymethyl ⁇ -thiazole-4-carboxylic acid methyl ester.
• Example 75 4-(4-Hydroxymethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 - ylmethyl)-3, 4-dihydro-naphthalen-2-yl]- lH-pyridin-2-one.
• Example 76 l-(6-Dimethylaminomethyl-3, 4-dihydro-naphthalen-2-yl)-4-(4-methoxy methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one.
• MCHR1 pIC ⁇ Determination FLIPRTM Assay (HEK293 cells): HEK293 cells stably transfected with hMCHRl were propagated as adherent cultures at 37°C in a humidified incubator. Cells were split 1 : 8 at 90% confluency two times per week. New cell stocks were recovered from storage every two months. Cells were plated in black 384-well plates (Greiner) 24 hours prior to assay at 15,000 cells/well in 50 ⁇ DMEM/F12, 10% FBS, 2 mM 1-glutamine. Compounds to be profiled were prepared by making a stock solution at 3xl0 "3 M in 100% DMSO.
• the stock solutions were serially diluted 1 :4 in 100% DMSO using JANUS (PerkinElmer) liquid handling instrument to allow for an 11 point curve in singlicate.
• the media was removed from the cell plate by aspiration, followed by the addition of 20 ⁇ ⁇ of loading buffer (Calcium 4 Kit, Molecular Dynamics corporation). Following 50 min incubation at 37°C, 10 ⁇ . of compound was added to the plates via the FLIPRTM instrument (Molecular Dynamics corporation). The plates were incubated at room temperature for 15 minutes along with an MCH peptide agonist challenge plate. On the FLIPRTM, a basal response was collected over 10 seconds followed by the addition of 10 ⁇ of MCH challenge concentration at 4XECso. Data was collected over 4 minutes and subjected to a nonlinear regression analysis curve fitting program to generate pIC 5 oS.
• B MCHR1 pIC ⁇ Determination Reporter Gene Assay: The assay consists of stable CHO cell line expressing hMCHRl and the inducible reporter Gal-4/Elk- 1 -luc plated at ten thousand cells/well in DMEM/F12, 5% FBS, 2 mM 1-glutamine in black 384-well assay plates. The day after plating, the media was removed by aspiration seventeen hours prior to assay, followed by the addition of 50 ⁇ of media without serum to reduce background signal noise. Compounds were prepared by making a stock solution at 3xl0 "3 M.
• the stock solutions is serially diluted 1 :4 in 100% DMSO using the JANUS liquid handling instrument (Perkin Elmer) to allow for an 11 point curves in singlicate.
• compounds 0.5 ⁇
• compounds were pipetted into the assay plate using JANUS.
• 10 ⁇ of 6xEC 8 o concentration (6x50nM) of MCH was added to the plate allowing for appropriate controls.
• the plates were then incubated under the same conditions for five hours. Under subdued light conditions, the compound/assay solution was removed by aspiration from the plates, followed by the addition of 15 ⁇ per well
• Exemplified compounds of the present invention were tested at one or more of the assays described above and were found to be functional antagonists of MCH at the MCHRl receptor with pICsoS >5.5.
• Examplar compounds with specific biological activities tested according to assays described herein are listed in Table 7 with pICsoS ranged from 6 to 8.7.

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